Effect of certolizumab pegol over 96†weeks in patients with psoriatic arthritis with and without prior antitumour necrosis factor exposure.

OBJECTIVE: Previous reports of RAPID-PsA (NCT01087788) demonstrated efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with psoriatic arthritis (PsA), including patients with prior antitumour necrosis factor (TNF) therapy. We report efficacy and safety data from a 96-week data cut of RAPID-PsA. METHODS: RAPID-PsA was placebo-controlled to week 24, dose-blind to week 48 and open-label to week 216. We present efficacy data including American College of Rheumatology (ACR)/Psoriasis Area and Severity Index (PASI) responses, HAQ-DI, pain, minimal disease activity (MDA), modified total Sharp score (mTSS) and ACR responses in patients with/without prior anti-TNF exposure, in addition to safety data. RESULTS: Of 409 patients randomised, 273 received CZP from week 0. 54 (19.8%) CZP patients had prior anti-TNF exposure. Of patients randomised to CZP, 91% completed week 24, 87% week 48 and 80% week 96. ACR responses were maintained to week 96: 60% of patients achieved ACR20 at week 24, and 64% at week 96. Improvements were observed with both CZP dose regimens. ACR20 responses were similar in patients with (week 24: 59%; week 96: 63%) and without (week 24: 60%; week 96: 64%) prior anti-TNF exposure. Placebo patients switching to CZP displayed rapid clinical improvements, maintained to week 96. In patients with ≥3% baseline skin involvement (60.8% week 0 CZP patients), PASI responses were maintained to week 96. No progression of structural damage was observed over the 96-week period. In the Safety Set (n=393), adverse events occurred in 345 patients (87.8%) and serious adverse events in 67 (17.0%), including 6 fatal events. CONCLUSIONS: CZP efficacy was maintained to week 96 with both dose regimens and in patients with/without prior anti-TNF exposure. The safety profile was in line with that previously reported from RAPID-PsA, with no new safety signals observed with increased exposure. TRIAL REGISTRATION NUMBER: NCT01087788.

Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA).

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-PsA (NCT01087788), an ongoing Phase 3 trial in patients with psoriatic arthritis (PsA). METHODS: Patients were randomised 1:1:1 to placebo, 200 mg CZP every 2 weeks (Q2W) or 400 mg CZP every 4 weeks (Q4W). Patients could have had exposure to one previous tumour necrosis factor (TNF) inhibitor therapy. Primary endpoints were American College of Rheumatology 20% (ACR20) response at week 12 and modified Total Sharp Score change from baseline at week 24. Secondary endpoints included; Psoriatic Arthritis Response Criteria (PsARC) score, Health Assessment Questionnaire Disability Index (HAQ-DI), Psoriasis Area and Severity Index, Leeds Enthesitis Index, Leeds Dactylitis Index, and Modified Nail Psoriasis Severity Index. RESULTS: Of 409 patients randomised, 368 completed 24 weeks of treatment. ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo (58.0% and 51.9% vs 24.3% (p<0.001)) at week 12, with improvements observed by week 1. There was a statistically significant improvement in physical function from baseline, measured by HAQ-DI in CZP patients compared with placebo (-0.50 vs -0.19, p<0.001) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo (78.3% and 77.0% vs 33.1% (p<0.001)). Sustained improvements were observed in psoriatic skin involvement, enthesitis, dactylitis and nail disease. Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure. No new safety signals were observed. CONCLUSIONS: Rapid improvements in the signs and symptoms of PsA, including joints, skin, enthesitis, dactylitis and nail disease were observed across both CZP dosing regimens.

The role of the dermatologist in identification and treatment of the early stages of psoriatic arthritis.

Early diagnosis of psoriatic arthritis (PsA) is essential for preventing disease progression and joint destruction. The majority of patients develop PsA years after the onset of their skin disease. Therefore, dermatologists are in a strategic position to make the diagnosis of PsA, and either manage it or refer the patient to a rheumatologist in order to prevent the potentially irreversible destruction of the affected joints. We will review the presentation and temporal relationship of psoriasis and PsA, the diagnosis, classification, and management, in addition to the role of the dermatologist in the early detection of PsA.

A comparison of the frequency of antibodies to cyclic citrullinated peptides using a third generation anti-CCP assay (CCP3) in systemic sclerosis, primary biliary cirrhosis and rheumatoid arthritis.

The objective was to investigate the frequency of anti-cyclic citrullinated peptides (CCP) antibodies in systemic sclerosis (SSc) and primary biliary cirrhosis (PBC), utilizing a new "third generation" anti-CCP ELISA (anti-CCP3) kit and a conventional anti-CCP2 assay. Patients with PBC, SSc, RA, and normal controls were included in the study. Serum samples were screened for autoantibodies by indirect immunofluorescence (IIF), antibodies to CCP by a second- and third-generation ELISA, antibodies to "scleroderma" antigens (CENP B, Scl-70, PM/Scl and fibrillarin-Scl-34) by a line immunoassay (LIA), and IgM RF by ELISA. The frequency of anti-CCP2 antibodies in SSc and PBC samples was 14.8% (11/74) and 6.2% (5/80), respectively, and the frequency of anti-CCP3 antibodies in SSc was 13.5% (10/74) and in PBC was 3.7% (3/80). By comparison, in the RA group the frequency of anti-CCP3 and anti-CCP2 antibodies was 79.1% (38/48) and 77% (37/48), respectively. Anti-CCP3 ELISA had a sensitivity, specificity, and positive and negative likelihood ratios (LR) of 79% (95% confidence interval [CI] = 64-89%), 93% (95% CI = 88-96%), 11.8 (95% CI = 6.8-20.3), and 0.22 (95% CI = 0.12-0.38), respectively. By comparison, the anti-CCP2 assay had a sensitivity, specificity, and positive and negative LRs of 77% (95% CI = 62-87), 90% (95% CI = 85-94), 8.3 (95% CI = 5.2-13.2), and 0.25 (95% CI = 0.15-0.42), respectively. In patients with SSc, there was an association of anti-CCP2 antibodies with the presence of arthritis, but there was no association of anti-CCP2 or anti-CCP3 with anti-CENP B, anti-Scl 70, or RF. This study confirmed the high specificity and sensitivity of both anti-CCP assays for the diagnosis of RA. The presence of anti-CCP antibodies in SSc was only correlated with the presence of arthritis.

CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis.

A recent genomewide scan in psoriatic arthritis (PsA) revealed a susceptibility locus at 16q. This region overlaps CARD15, a susceptibility gene in Crohn disease. The possibility of a common susceptibility gene between PsA and Crohn disease is further supported by epidemiological studies that note an increased incidence of psoriasis in subjects with Crohn. We screened 187 patients with PsA and 136 healthy controls, all from Newfoundland, for the three common, independent sequence variants of CARD15 (R702W, leu1007fsinsC, and G908R), which were detected by polymerase chain reaction by use of allele-specific primers and visualized through gel electrophoresis. In total, 53/187 (28.3%) probands with PsA had at least one variant of the CARD15 gene, compared with 16/136 (11.8%) controls (odds ratio 2.97; 95% confidence interval 1.61-5.47; P=.0005). Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with PsA, compared with 3.31%, 2.57%, and 0.37%, respectively, in the control patients. CARD15 conferred susceptibility to PsA independent of HLA-Cw*0602. Thus, CARD15 represents a pleiotropic autoimmune gene and is the first non-MHC gene to be associated with PsA.

Probing for genes in seronegative spondyloarthropathy.

Seronegative spondyloarthropathies are a group of disorders characterized by inflammation of the spine, sacroiliac joints, and peripheral arthritis along with various characteristic extra-articular features. Their pathogenesis and immunogenetics have not yet been fully elucidated. Ankylosing Spondylitis (AS) is probably the best studied of these disease. It has now been 27 years since the association of human leukocyte antigen (HLA) B27 and AS has been demonstrated. Since then, a plethora of association studies and linkage studies unequivocally demonstrate that genetic determinants within or near the major histocompatible complex (MHC) are critical to the etiology of AS. Surprisingly though, the total MHC contribution to AS has been estimated at only 30%. In this review, we highlight the genetic basis of AS as the prototypical chronic axial arthritis, and discuss the rationale and approach in searching for non-HLA linked genes.

Systemic sclerosis (scleroderma) in two iron ore mines.

Six males with systemic sclerosis were observed in the work forces of two iron ore mines. The usual spectrum of clinical features encountered in systemic sclerosis patients were present. Histologic examination of pulmonary tissue was performed on three of the cases and showed features of both silicosis and scleroderma but to different degrees and stages of development. Exposure to high levels of silica-containing dusts had occurred in all six cases.

The role of anti-malarials in rheumatoid arthritis--the American experience.

Rheumatoid Arthritis (RA) is a chronic disease with significant morbidity and functional disability. The traditional treatment for RA relied on the use of NSAIDs early in the disease course, followed by disease-modifying agents later. More recently, the disease-modifying anti-rheumatic drugs (DMARDs) have become the mainstay of RA therapy because of the recognition of their superior efficacy/toxicity profile. The antimalarial drugs, chloroquine and hydroxychloroquine, are some of the most commonly used DMARDs in the management of RA. They have been shown to be significantly more effective than NSAIDs alone in several clinical trials, and have a benign toxicity profile. A combination of hydroxychloroquine with methotrexate appears to reduce significantly the hepatic toxicity of methotrexate. In this review, we summarize the efficacy and toxicity profiles of the antimalarial drugs in rheumatoid arthritis.

Primary angiitis of the CNS diagnosed by angiography.

Sixteen patients (8 female, 8 male) with primary angiitis of the CNS (PACNS), were followed prospectively in a vasculitis clinic. Diagnosis was by angiography in patients without underlying disease. Median age at diagnosis was 36.5 years, and median duration of follow-up was 28 months. Onset was acute in 14 patients (88%), with 3.5 weeks (median) from onset symptoms to diagnosis. Three women developed symptoms within 3 weeks postpartum. The most frequent symptoms were severe headaches (12, 75%), stroke (6, 30%), transient ischaemic attack (TIA) (4, 28%), seizures (7, 44%), visual aberration (3, 19%), and cognitive impairment (5, 31%). Laboratory data included high ESR (2, 13%), leucocytosis (8, 80%), thrombocytosis (1, 6%), positive antinuclear antibody titre (3, 15%), and high levels of complement (5, 31%). Lumbar puncture was performed in 12 patients (75%). CSF analysis was abnormal in five patients (42%). EEG was abnormal in 5/9 patients. The major CT/MRI scan findings were cerebral haemorrhage (4, 25%), brain infarcts (5, 31%), brain atrophy (2, 13%) and non-specific lesions (2, 13%). Four patients had normal studies. All patients received corticosteroids (CS), and five were treated with oral cyclophosphamide. Two patients relapsed despite CS and cyclophosphamide therapy. All patients are alive, and at the last assessment, eight had a permanent neurological deficit, which included paresis (3, 19%), neurocognitive abnormalities (2, 13%), visual loss (2, 13%) and seizure activity (5, 31%). Our data suggest a non-progressive, non-fatal course in those PACNS patients diagnosed angiographically and treated with CS with or without cyclophosphamide.

Lymphadenopathy, oligoclonal T cell receptor rearrangement and systemic lupus erythematosus.

To investigate the cause of generalized lymphadenopathy in case of systemic lupus erythematosus (SLE), we performed a molecular genetic analysis of lymph node, peripheral blood mononuclear cell and bone marrow specimens with T cell receptor and immunoglobulin gene probes. Oligoclonal T cell receptor rearrangements were detected in the lymph node cells. The oligoclonal T cell expansion observed is the first such example reported in SLE, and may be indicative of an immune response to specific antigenic challenge. Alternatively, these changes may represent the earliest phases of a malignant process. Molecular genetic investigations in autoimmune disease such as SLE can provide opportunities to enhance our understanding of the underlying condition, or reveal unexpected abnormalities requiring further assessment.

A patient with Werner's syndrome and osteosarcoma presenting as scleroderma.

Werner's syndrome (WS) is often mistaken for scleroderma. We describe a patient with WS who presented with an enlarging, painful mass of the right knee that proved to be a juxtaarticular osteosarcoma of the distal femur. Recognition of WS and prompt investigation of any painful, enlarging masses to exclude sarcomatous degeneration will benefit these patients.

HLA antigens in North American patients with Takayasu arteritis.

OBJECTIVE: To determine the frequency of HLA class I and II antigens in Caucasian North American patients with Takayasu arteritis (TA). METHODS: Seventy-three class I antigens and 13 class II antigens were examined in 21 Caucasian North American patients with TA, and their frequencies were compared with findings in 243 healthy, untreated controls. HLA typing was performed by microlymphocytotoxicity assay. RESULTS: We found no statistically significant positive association of TA with DR2, DR4, DQw3, or any of the other class I or class II antigens studied. A negative association between TA and DR1 was noted. There was no significant association between any of the HLA antigens and the severity of the disease or the presence of complications. CONCLUSION: The negative association between TA and the DR1 antigen suggests that this antigen may be protective against the development of the disease.

Inclusion body myositis in association with vitamin B12 deficiency and Sjögren's syndrome.

Autoimmune disorders are very rarely associated with inclusion body myositis (IBM). We describe a patient with IBM in association with Sjögren's syndrome (SS) and Vitamin B12 deficiency. B12 deficiency has not been reported in SS, and this deficiency may explain the neuropathic features of some patients with IBM.

Treatment of fulminant adult Still's disease with intravenous pulse methylprednisolone therapy.

We describe a patient with fulminant adult onset Still's disease and multiple organ involvement. The acute flare persisted despite high doses of prednisone but responded to megadose intravenous pulse methylprednisolone therapy. This treatment modality may be useful in temporizing severe multisystem exacerbations of adult Still's disease.